Conceptual knowledge is underpinned by the temporal pole bilaterally: Convergent evidence from rTMS

Conceptual knowledge provides the basis on which we bring meaning to our world. Studies of semantic dementia patients and some functional neuroimaging studies indicate that the anterior temporal lobes, bilaterally, are the core neural substrate for the formation of semantic representations. This hypothesis remains controversial, however, as traditional neurological models of comprehension do not posit a role for these regions. To adjudicate on this debate, we conducted 2 novel experiments that used off-line, low-frequency, repetitive transcranial magnetic stimulation to disrupt neural processing temporarily in the left or right temporal poles (TPs). The time required to make semantic decisions was slowed considerably, yet specifically, by this procedure. The results confirm that both TPs form a critical substrate within the neural network that supports conceptual knowledge

Evaluating synergy between deregulation of the Wnt, PI3-Kinase and MAP-Kinase pathways in prostate tumourigenesis

The Wnt, PI3-Kinase (PI3K) and MAP-Kinase (MAPK) cell signalling pathways play important roles in human prostate cancer (PCa). In this thesis, analysis of a human PCa tissue micro-array (TMA) constructed by the Welsh Cancer Bank demonstrated upregulation of markers associated with these pathways in PCa. There was also greater expression of these markers in high-risk tumours with some being predictive of biochemical recurrence following surgery. Furthermore, there is evidence to support cross talk between these pathways allowing clustering into low- and high-risk samples based on expression profiles. Targeted next generation sequencing (NGS) also demonstrated recurrent mutations of genes associated with these pathways in PCa. Conditional transgenic mouse models were employed to explore the complex communication between these pathways. The loss of Pten was incorporated as a means of activating the PI3K pathway, and mutated β-catenin and K-Ras as means of aberrant Wnt and MAPK signalling. This study provides the first evidence of crosstalk and cooperation between these pathways, resulting in a significant effect on prostate tumourigenesis. Mice with loss of Pten in addition to activated mutations of β-catenin and K-Ras (Triple mutants) have significant upregulation of all three pathways resulting in a shorter survival compared to single and double mutants. The feasibility of these models allows further specific gene profiles to be induced in the mouse, providing a platform for pre-clinical testing of novel therapeutic agents. The effect of deregulation of these pathways on the cancer stem cell (CSC) population was explored using fluorescence-activated cell sorting (FACS) and organoid culture. Compound mutant (doubles and triple) tumours have a greater number of CSC or enriched cells compared to single mutant or wildtype (WT) mice. Compound mutant tumours had greater organoid forming efficiency than single mutants however this was significantly inferior to WT cells. Overcoming the difficulty experienced in cultivating tumour organoids will help manufacture targeted drugs with the aim of forming a cryopreserved organoid library to facilitate precision medicine

The role of the anterior temporal lobes in the comprehension of concrete and abstract words: rTMS evidence

Conceptual knowledge allows us to bring meaning to our world. Studies of semantic dementia (SD) patients and some functional neuroimaging studies indicate that the anterior temporal lobes, bilaterally, are a core neural substrate for the formation of conceptual representations. The majority of SD patients (who have circumscribed atrophy of the anterior temporal lobes) have better comprehension of concrete than abstract words. However, this finding remains controversial, as some individual SD patients have exhibited reverse imageability effects, i.e., relative preservation of abstract knowledge. This would imply that the anterior temporal lobes are particularly crucial for processing sensory aspects of semantic knowledge, which are an important part of concrete but not abstract concepts. To adjudicate on this debate, we used offline, low-frequency, repetitive transcranial magnetic stimulation to disrupt neural processing temporarily in the left or right temporal poles (TPs). We examined this effect using a synonym judgement task, comprising high, medium and low imageability items, which we have previously employed with a case-series of SD patients. The time required to make semantic decisions was slowed considerably, particularly for low imageability items, consistent with the pattern we observed in SD. These results confirm that both TPs make a critical contribution to semantic processing, even for abstract concepts that do not have strong sensory representations

Remembering 'zeal' but not 'thing':reverse frequency effects as a consequence of deregulated semantic processing

More efficient processing of high frequency (HF) words is a ubiquitous finding in healthy individuals, yet frequency effects are often small or absent in stroke aphasia. We propose that some patients fail to show the expected frequency effect because processing of HF words places strong demands on semantic control and regulation processes, counteracting the usual effect. This may occur because HF words appear in a wide range of linguistic contexts, each associated with distinct semantic information. This theory predicts that in extreme circumstances, patients with impaired semantic control should show an outright reversal of the normal frequency effect. To test this prediction, we tested two patients with impaired semantic control with a delayed repetition task that emphasised activation of semantic representations. By alternating HF and low frequency (LF) trials, we demonstrated a significant repetition advantage for LF words, principally because of perseverative errors in which patients produced the previous LF response in place of the HF target. These errors indicated that HF words were more weakly activated than LF words. We suggest that when presented with no contextual information, patients generate a weak and unstable pattern of semantic activation for HF words because information relating to many possible contexts and interpretations is activated. In contrast, LF words tend are associated with more stable patterns of activation because similar semantic information is activated whenever they are encountered